This project aims to apply classical and quantum chemical techniques to structural questions related to HIV pathogenesis, in particular those involving HIV-1 protease and the HIV-1 reverse transcriptase. We are currently performing quantum mechanical calculations on models of the active site in an effort to define the transition state of the protease. Knowing how the hydrolysis takes place should motivate the design of blocking agents. We have built small models of the active site which identified the key intermediates in the reaction cycle. We plan to expand the model to include more of the environment of the key residues. We are also working with the Kunkel/ Bebenek lab to model the HIV-RT/DNA interaction in the "thumb" domain in order to provide a structural basis for discussing the results of their mutagenesis studies relating to polymerase processivity and fidelity.